The ergot alkaloids have a complex mode of action that involves interaction with a variety of receptors (86). Indeed, as shown in Table 50-1 (2,37,56,57,73,74), both ergotamine and dihydroergotamine have affinities for 5-hydroxytryptamine (5-HT), dopamine, and noradrenaline receptors. In contrast, sumatriptan is much more selective, showing high affinity for 5-HT_1B and 5-HT_1D receptors and a moderate affinity for 5-HT_1A and 5-HT_1F receptors.

The α-adrenoceptor blocking property of ergotamine, first described in 1906 (19), is textbook knowledge (53); however, this property is often overemphasized, in that it has been observed with high doses used in some animal models, which bears no relevance to therapeutic use in humans (32). In lower therapeutically relevant concentrations, ergotamine acts as an agonist at α-adrenoceptors, 5-HT (particularly 5-HT_1B/1D) and dopamine D₂ receptors (22,85,86,101,129). In addition, there is evidence that both ergotamine and dihydroergotamine can activate novel, not yet characterized receptors (22).

The most important and conspicuous pharmacologic effect of ergot alkaloids is undeniably the vasoconstrictor action (85,86). Extensive studies in animal models have shown that this vasoconstrictor effect is particularly marked within the carotid vascular bed. This selectivity further extends to the arteriovenous anastomotic part of the carotid circulation; blood flow to a number of tissues, including that to the brain, is affected only minimally (22,63,128). Similar vasoconstrictor effects on cephalic arteriovenous anastomoses also have been observed with the use of sumatriptan as well as other triptans (102).

In humans, ergotamine can constrict several isolated blood vessels, including the pulmonary (16), cerebral (85), temporal (87), and coronary (79) arteries. The drug seems to be more active on large arteries (conducting vessels) than on arterioles (resistance vessels). Dihydroergotamine constricts veins as demonstrated locally by local infusion into hand veins (3) and its contractile effect on human basilar arteries is equipotent, but with a smaller maximal effect than ergotamine (85).

In humans, arterial blood pressure is transiently increased moderately after parenteral therapeutic doses of
ergotamine and dihydroergotamine (6,112,114). For ergotamine, the hypertensive response is caused by increased total peripheral resistance (116). Basal cerebral blood flow (CBF) and acetazolamide-stimulated CBF also is unchanged after both ergotamine and dihydroergotamine (6). Basal myocardial blood flow also is unchanged after intravenous ergotamine, but the coronary vasodilator reserve decreases, probably by an effect on the microcirculation (38). In contrast to the short-lasting (about 3 hours) effect on blood pressure, ergotamine causes a long-lasting (at least 24 hours) vasoconstriction of leg arteries (112,114,122). A similar long-lasting venoconstrictor effect (at least 8 hours) has been observed after a single dose of dihydroergotamine (5). For dihydroergotamine no effect on peripheral arteries was found (6). An important feature of ergotamine and dihydroergotamine, observed in vitro is that their effect on blood vessels is resistant to repeated wash (79,84,87), which appears to be caused mainly by slow diffusion from the receptor biophase; therefore,
their effects last far longer than can be expected from plasma concentrations (5,118).

Ergotamine and dihydroergotamine have been reported to inhibit dural plasma extravasation after stimulation of the trigeminal ganglion in rat (12,13,81) by a C-fiber-dependent mechanism, perhaps coupled to blockade of neuropeptide release from perivascular nerves (see Chapter 17). Furthermore, dihydroergotamine binds to receptors in the trigeminal nucleus caudalis and in the dorsal horn of the first and second cervical segments of the spinal cord in the cat (39), which, in turn, may inhibit activity in the central trigeminal neurons (55) (see Chapter 23). Probably, ergotamine has the same effect. Both the peripheral and central effects on the trigeminovascular system have been suggested to contribute to the antimigraine effect of ergot alkaloids.